Sjögren‐Larsson syndrome (SLS) is a rare neurometabolic syndrome caused by deficient fatty aldehyde dehydrogenase. Patients exhibit intellectual disability, spastic paraplegia, and ichthyosis. The accumulation of fatty alcohols and fatty aldehydes has been demonstrated in plasma and skin but never in brain. Brain magnetic resonance imaging and spectroscopy studies, however, have shown an abundant lipid peak in the white matter of patients with SLS, suggesting lipid accumulation in the brain as well. Using histopathology, mass spectrometry imaging, and lipidomics, we studied the morphology and the lipidome of a postmortem brain of a 65‐year‐old female patient with genetically confirmed SLS and compared the results with a matched control brain. Histopathological analyses revealed structural white matter abnormalities with the presence of small lipid droplets, deficient myelin, and astrogliosis. Biochemically, severely disturbed lipid profiles were found in both white and gray matter of the SLS brain, with accumulation of fatty alcohols and ether lipids. Particularly, long‐chain unsaturated ether lipid species accumulated, most prominently in white matter. Also, there was a striking accumulation of odd‐chain fatty alcohols and odd‐chain ether(phospho)lipids. Our results suggest that the central nervous system involvement in SLS is caused by the accumulation of fatty alcohols leading to a disbalance between ether lipid and glycero(phospho)lipid metabolism resulting in a profoundly disrupted brain lipidome. Our data show that SLS is not a pure leukoencephalopathy, but also a gray matter disease. Additionally, the histopathological abnormalities suggest that astrocytes and microglia might play a pivotal role in the underlying disease mechanism, possibly contributing to the impairment of myelin maintenance.

中文翻译：

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Sjögren-Larsson 综合征脑醚脂质代谢和组织学紊乱。

Sjögren-Larsson 综合征 (SLS) 是一种罕见的神经代谢综合征，由缺乏脂肪醛脱氢酶引起。患者表现出智力障碍、痉挛性截瘫和鱼鳞病。脂肪醇和脂肪醛的积累已在血浆和皮肤中得到证实，但从未在大脑中得到证实。然而，脑磁共振成像和光谱学研究表明，SLS 患者的白质中存在丰富的脂质峰，这表明脂质也在大脑中积聚。我们使用组织病理学、质谱成像和脂质组学研究了一名 65 岁的 SLS 女性患者死后大脑的形态学和脂质组，并将结果与​​匹配的对照大脑进行比较。组织病理学分析显示结构性白质异常，存在小脂滴、髓鞘缺陷和星形胶质细胞增生。在生化方面，在 SLS 大脑的白质和灰质中都发现了严重紊乱的脂质谱，并伴有脂肪醇和醚脂质的积累。特别是长链不饱和醚类脂质积累，最突出的是在白质中。此外，奇数链脂肪醇和奇数链醚（磷）脂有惊人的积累。我们的研究结果表明，中枢神经系统参与 SLS 是由脂肪醇的积累引起的，导致醚脂质和甘油（磷酸）脂质代谢之间的失衡，从而导致大脑脂质组的严重破坏。我们的数据显示 SLS 不是一种单纯的白质脑病，但也是一种灰质疾病。此外，组织病理学异常表明星形胶质细胞和小胶质细胞可能在潜在的疾病机制中起关键作用，可能导致髓鞘维持受损。